Whereas non-suicidal self injury (NSSI) is reported in 13-23% of adolescents and is an increasingly studied topic, there has been little investigation into the pathophysiology behind self-injury. This commentary examines recent research into pain and emotional distress to discuss implications for the manner we should understand, research, and treat NSSI in the future. Research indicates that adolescents may be particularly vulnerable to NSSI behaviors due to neurodevelopmental changes in the processing of distress and pain. Additionally, emotional distress and physical pain neural pathways may have been altered in these individuals, leading to the development of NSSI behaviors during adolescence when changes in ongoing brain development may lead to further emotional dysregulation and poor impulse control. Further studies that directly characterize the relationship between emotional distress and physical pain in adolescence, as well as the neural differences between self-injurers and non-self-injurers, are needed.